Project Summary Traumatic brain injury (TBI) currently affects 1.6-3.8 million people in the US annually. Over the past 30 years, research has linked TBI to a greater risk of developing Alzheimer?s disease (AD) or another dementia years after the original head injury. More recently, emerging evidence shows that TBI increases intestinal permeability and alters gut microbiome composition that further exacerbate inflammation, brain vascular/metabolic dysfunctions and perpetuate long-term secondary sequelae. Therefore, the presumption is that having a pre-existing healthy gut microbiome composition/diversity may be critical for protecting brain functions after TBI and potentially prevent the further development of cognitive impairment. In this study, our goal is to determine if AD risk can be reduced by administrating prebiotic Inulin diet before TBI in young mice to protect the brain vascular, metabolic, and white matter (WM) integrity and reduce neuroinflammation through gut microbiome modulation. The central hypothesis is that mice with inulin diet before TBI will have healthier gut microbiome profile and better protection for brain vascular, metabolic and WM integrity after TBI, and thus protect the cognitive function. We will test the hypothesis by pursuing the following two Specific Aims: (i) Determine Inulin effects on the gut microbiome and SCFAs production for protecting TBI; (ii) Identify Inulin effects on brain functions and neuroinflammation for protecting TBI. This project is innovative because it is one of the first studies to identify the protective effects of prebiotic Inulin for TBI via gut-brain axis. It is also innovative because it challenges the current standing of the field of TBI. Instead of trying to reduce the neurological and systemic effects of injury after it occurs, we shift the focus to mitigation of the injury cascade in populations already known to be at risk such as military personnel and athletes. The success of the study would enhance our understanding of CNS-peripheral interactions in TBI, and identify potential effective dietary intervention for preventing AD in a younger population. As Inulin-related diets are commercially available, and MRI neuroimaging and gut microbiome analyses are readily to be used for humans, our approaches are highly translational; if we are able to show that we can use diet as a measure to mitigate secondary sequelae in mice, we?d be able to rapidly transition to studies with humans.